Recovery, not progressive deterioration, should be the expectation in schizophrenia

Since the time of Kraepelin, schizophrenia has been considered to be a progressive deteriorating illness (1). This perspective has been bolstered by a generation of studies demonstrating deficits in brain volumes on magnetic resonance imaging (MRI) scans and in performance on a broad range of cognitive tasks in individuals with schizophrenia (2).

Despite the introduction of effective pharmacological treatments and evidence-based psychosocial interventions, fewer than one in seven people affected are considered to meet criteria for recovery (3). The possibility that the pathophysiology of schizophrenia involves mechanisms that progress over the longitudinal course of the illness is often assumed to explain the poor outcomes observed (2). Advocates for early intervention have embraced this paradigm as it implies that early treatment has the potential to arrest a disease process that would otherwise continue on an unrelenting march to severe mental deterioration.

While progression of an active disease process would provide a compelling explanation for the poor outcomes so commonly observed, it is not consistent with what we have learned from modern studies of the longitudinal course of structural brain abnormalities, cognitive deficits and clinical outcomes associated with schizophrenia (4). Rather, schizophrenia appears to be associated with stability of these measures over the longer term. It is time to consider the possibility that clinical stability and recovery rather than progressive deterioration should be the expected outcomes from schizophrenia.

STRUCTURAL BRAIN FINDINGS IN SCHIZOPHRENIA

Modern in vivo brain imaging technology has provided opportunities to study differences in brain structure in people with schizophrenia and to assess changes in these measures over time. Increases in cerebrospinal fluid (CSF) volumes, together with deficits in both gray matter and white matter volumes, have been reported in patients with chronic schizophrenia and are present to a lesser degree in individuals studied at the time of their first episode of psychosis (5).

The relatively greater differences in brain tissue and CSF volumes in more chronically ill patients could be the result of progression of these differences over the course of the illness. Alternatively, it could be the case that those individuals with more striking differences at the time of the first episode are more likely to have a poor outcome and, as a consequence, are over-represented in more chronically ill samples.

This issue appeared to be resolved when a number of large longitudinal MRI studies reported progressive reductions in brain tissue volumes in patients following a first episode of psychosis compared to healthy controls (6,7). However, subsequent studies in patients (8) and in animals (9,10) have demonstrated that antipsychotic medications can lead to these imaging findings, which may also be reversible to some degree (11,12). The increases observed in the magnitude of structural brain findings over the course of schizophrenia may be better explained by medication effects, together with differences in exposure to alcohol, drugs of abuse, smoking and levels of activity (4).

COGNITIVE DEFICITS IN SCHIZOPHRENIA

The magnitude of cognitive deficits observed in people with schizophrenia has been observed to be associated with measures of community functioning (13) and with the extent of the structural brain differences (14).

Cognitive deficits, like the structural brain differences, are clearly evident at the time of the first episode of psychosis. These deficits are observed to improve to a significant degree in the first year of treatment (15) and have been found to remain stable or improve rather than decline over the longer term (16).

When the cognitive deficits associated with schizophrenia initially develop remains unclear. Some of the deficits are likely apparent early in childhood, while others may reflect a subsequent lag in developmental processes that results in the finding of even greater deficits relative to healthy controls by the time individuals present with a first episode of psychosis (17).

There does not appear to be any period in the developmental trajectory of individuals with schizophrenia during which absolute measures of cognitive performance are actually declining.

CLINICAL OUTCOMES FROM SCHIZOPHRENIA

If both structural brain measures and cognitive functioning are likely to remain stable following the onset of schizophrenia, then why should ongoing deterioration in functioning occur? It is well established that 70-80% of individuals with a first episode of schizophrenia will experience a remission of psychotic symptoms within the first year of treatment (18). This percentage seems to remain stable when individuals are provided with ongoing comprehensive treatment (19). Relapse of psychotic symptoms following a remission from a first episode of schizophrenia is also observed to occur in over 80% of individuals when studied naturalistically (20). This is largely attributable to discontinuation of antipsychotic medication rather than to the effects of an unrelenting disease process. The risk of symptom recurrence in remitted first episode patients receiving maintenance antipsychotic treatment is estimated to be in the range 0-5% in the first year of follow-up, compared to 78% in the first year off medication and close to 100% after three years off medication (21).

While we may be inclined to try to eventually discontinue antipsychotic medication for those patients who have the best response and remission, this may be misguided. It should not be surprising that those patients who respond most robustly to dopamine D2 antagonists may also be most likely to become ill when those same medications are discontinued. With antipsychotic medication, the large majority of individuals with a first episode of schizophrenia are able to achieve and sustain symptomatic remission. Without medication, few if any patients with a diagnosis of schizophrenia are likely to remain in remission. The total number of patients who are able to achieve remission would be expected to be even higher with early use of clozapine for those patients who fail to remit with first-line antipsychotics (22).

If schizophrenia were by nature a progressive deteriorating illness, then the percentage of patients who achieve remission and recovery should decline with increasing duration of illness, and the percentage with poor outcomes should increase. This does not appear to be the case: the percentage of patients who meet criteria for poor outcome, remission, functional recovery, and recovery does not vary with the duration of follow-up (3,23).

If the majority of patients remit and have the potential to remain in remission, then why have outcomes remained poor for so many? There are many reasons to consider. Many people with schizophrenia are not in treatment, either because services are not available to them or they have chosen not to be involved. Of those who are treated, 20-30% are poor responders to antipsychotic medications. Others have repeated challenges with treatment non-adherence, with consequent relapses and re-hospitalizations. For many, the course of illness is distorted by concurrent problems with substance abuse, intellectual disability, depression and other mental illnesses, in addition to the challenges posed by stigma, poverty and diminished opportunities (24).

WHAT IS “RECOVERY”?

Despite enormous optimism about the potential for comprehensive early intervention programs to improve real world outcomes, it does appear that recovery from schizophrenia is far less common than remission. Relapses and hospitalizations may be largely preventable, but the level of functioning that clinically stable individuals are likely to attain is less clear.

The percentage that will achieve competitive employment would be expected to vary depending on the criteria used (e.g., full-time versus part-time, duration of employment, level of income). When “recovery” is defined as a persistence of symptom remission together with social and vocational improvement, fewer than 15% of individuals with schizophrenia meet this definition (3). The possibility that many remitted patients have goals that differ from those embodied in current definitions of “recovery” may in part explain this finding.

Individuals who have experienced a remission from a first episode of schizophrenia report levels of happiness, satisfaction, success, and positive daily affect that are comparable to age-matched controls, as well as less negative affect throughout their day, despite functioning at much lower levels (25). Data collected as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study in the U.S. found that, on average, patients reported their level of satisfaction with life/happiness as mixed (i.e. neither satisfied nor dissatisfied with life in general) (26). That self-reported levels of happiness and life satisfaction are not lower may reflect a process of personal adaptation to having a potentially chronic and disabling illness. Preserved levels of happiness and satisfaction in the face of low levels of functioning may also reflect cognitive, socioeconomic and cultural differences.

How recovery from schizophrenia is envisioned is likely to vary greatly between individuals. Psychiatrists have typically embraced a “medical” model of recovery that emphasizes the elimination of symptoms and a return to normal levels of functioning; patients-consumers may find a “rehabilitation model of recovery” more compelling, with its emphasis on creating a meaningful and satisfying life in one's community (27). Identifying those personal goals that are of most importance to each individual patient is critical, as outcomes that are not a personal priority are unlikely to be realized.

While there is room for debate about how recovery should be defined, it should be clear that most individuals with schizophrenia have the potential to achieve a stable remission of symptoms and substantial levels of satisfaction and happiness. Future outcome studies will need to incorporate outcomes that reflect the patient experience. Societal resources will also need to be allocated to support the realization of a broader patient-centered conception of recovery.